Neuronal and molecular mechanisms underlying chronic pain and depression comorbidity in the paraventricular thalamus.

Patients with chronic pain often develop comorbid depressive symptoms, which makes the pain symptoms more complicated and refractory. However, the underlying mechanisms are poorly known. Here, in a repeated complete Freund's adjuvant (CFA) male mouse model, we reported a specific regulatory role of the paraventricular thalamic nucleus (PVT) glutamatergic neurons, particularly the anterior PVT (PVA) neurons, in mediating chronic pain and depression comorbidity (CDC). Our c-Fos protein staining observed increased PVA neuronal activity in CFA-CDC mice. In wild-type mice, chemogenetic activation of PVA glutamatergic neurons was sufficient to decrease the 50% paw withdrawal thresholds (50% PWTs), while depressive-like behaviors evaluated with immobile time in tail suspension test (TST) and forced swim test (FST) could only be achieved by repeated chemogenetic activation. Chemogenetic inhibition of PVA glutamatergic neurons reversed the decreased 50% PWTs in CFA mice without depressive-like symptoms and the increased TST and FST immobility in CFA-CDC mice. Surprisingly, in CFA-CDC mice, chemogenetically inhibiting PVA glutamatergic neurons failed to reverse the decrease of 50% PWTs which could be restored by rapid-onset antidepressant S-ketamine. Further behavioral tests in chronic restraint stress mice and CFA pain mice indicated that PVA glutamatergic neuron inhibition and S-ketamine independently alleviate sensory and affective pain. Molecular profiling and pharmacological studies revealed the 5-hydroxytryptamine receptor 1D (Htr1d) in CFA pain-related PVT engram neurons as a potential target for treating CDC. These findings identified novel CDC neuronal and molecular mechanisms in the PVT and provided insight into the complicated pain neuropathology under a comorbid state with depression and related drug development. Significance Statement Patients with chronic pain frequently experience concurrent depressive symptoms, which complicates the treatment of the pain symptoms. Recently, the paraventricular thalamic nucleus (PVT) has attracted growing interest in modulating animal behaviors of pain sensation and stress-related affective disorders. However, whether and how PVT mediate chronic pain and depression comorbidity (CDC) remains poorly understood. Here, utilizing chemogenetics, viral labelling, neuronal cell types-based TRAP (translating ribosome affinity purification) technology and pharmacological studies, our current study revealed that PVT is a central hub for regulating sensory pain and depressive-like behaviors but not affective pain by functioning through the 5-hydroxytryptamine receptor 1D (Htr1d). These findings provide new insights of the regulatory role of the PVT and a potential molecular target for future analgesic development.